CN116102530A - 氰基取代二苯并呫吨化合物及其应用 - Google Patents
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Abstract
本发明公开了式(Ⅰ)所示的氰基取代二苯并呫吨类化合物。本发明提出的氰基取代二苯并呫吨类化合物具有较高的抗肿瘤活性，在制备抗肿瘤药物中具有较好的前景。
其中：R为H、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3或CH2CH2OH；R1为H或CN，R2为CN。
Description
技术领域
本发明涉及有机化学合成和药物研发领域，尤其涉及一种氰基取代二苯并呫吨化合物及其应用。
背景技术
恶性肿瘤的危害已经成为了全球性的卫生问题，其死亡率仅次于心脑血管疾病。寻找选择性强，毒副作用小，价格低廉的高效抗肿瘤药物是药学界的一个重要的课题。二苯并呫吨化合物是一类重要的生物学活性杂环化合物，其具有镇痛，抗炎，抗肿瘤，抗菌和抗病毒活性的作用，更多的研究表明，二苯并呫吨类化合物具有广谱的抗肿瘤活性，能够抑制癌细胞的大量扩散，并诱导细胞凋亡。但是目前化合物还存在很多问题，水溶性低和对癌细胞毒性不够显著，因此需要解决此类问题使化合物能更好的开发应用。
目前来说，二苯并呫吨类化合物更多是通过铜胺络合物进行催化合成，条件比较温和，但是步骤多，反应时间长。同时，取代基仍需要做进一步的优化，提供更好的抗肿瘤活性。
发明内容
本发明提供了一种氰基取代二苯并呫吨化合物及其应用，本发明采用微波法，从原料一步合成得到目标产物，反应速度快，得到的该类化合物对肿瘤细胞具有比较显著的抑制活性。
本发明的第一个目的是提出了式(Ⅰ)所示的氰基取代二苯并呫吨化合物：
其中：R为H、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3或CH2CH2OH；R1为H或CN，R2为CN。
优选地，式(Ⅰ)所示的氰基取代二苯并呫吨化合物(氰基取代二苯并[a,kl]呫吨化合物)如表1所示：
表1
本发明还保护上述氰基取代二苯并呫吨化合物的制备方法，包括如下步骤：称取二水合氯化铜，溶于反应溶剂，然后加入乙醇胺，加热搅拌使其混合均匀生成铜胺络合物溶液，二水合氯化铜与乙醇胺的摩尔比为1:1，若溶液浑浊，补加反应溶剂，直至溶液澄清，称取原料加入铜胺络合物中，所述的原料为6-氰基-2-萘酚或2-萘酚和6-氰基-2-萘酚的混合物，溶解完全后，将反应容器置于微波炉中，TLC跟踪原料至反应完全，减压蒸馏，乙酸乙酯萃取，有机相用无水硫酸钠干燥，旋干，所得粗产品进行硅胶柱层析分离和洗脱，得到产物；
上述反应所涉及的反应方程式如下：
其中：R为H、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3或CH2CH2OH；R1为H或CN，R2为CN。
所述的减压蒸馏，乙酸乙酯萃取，有机相用无水硫酸钠干燥，旋干，所得粗产品进行硅胶柱层析分离和洗脱，得到产物的具体步骤是：减压旋转蒸发回收大部分反应溶剂，加入质量分数为5％的氨水，用乙酸乙酯萃取三次，水洗有机层至中性，用无水Na2SO4干燥有机相，减压旋转蒸发回收乙酸乙酯，残留物进行硅胶柱层析，洗脱剂为石油醚-乙酸乙酯，得到产物。
优选地，所述的2-萘酚与6-氰基-2-萘酚的摩尔比为1.1:1。
优选地，所述的二水合氯化铜或乙醇胺与原料的摩尔比为1:1。
优选地，所述的反应溶剂为水或ROH醇溶剂，R为CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3或CH2CH2OH。
优选地，所述的洗脱剂为石油醚-乙酸乙酯。
本发明还保护上述氰基取代二苯并呫吨化合物在制备抗肿瘤药物中的应用。
优选地，所述的应用具体为氰基取代二苯并呫吨化合物在制备抗宫颈癌药物、抗肝癌药物、抗胃癌药物或抗肺癌药物中的应用。
本发明还保护上述氰基取代二苯并呫吨化合物及其药学上可接受的盐组合成的药学上可接受的药物组合物或制剂在制备抗肿瘤药物的应用。
与现有技术相比，本发明的有益效果是：目前二苯并呫吨类化合物更多是通过铜胺络合物进行催化合成，条件比较温和，但是步骤多，反应时间长，本发明通过采用微波法，从原料一步合成得到目标产物，反应速度快。并且该类化合物对肿瘤细胞具有显著的抑制活性。
具体实施方式
下面结合实施例对本发明做进一步详细的描述。这些实施例仅用于说明本发明而不用于限制本发明的范围。以下实施例中未注明具体条件的实验方法，通常按照本领域常规条件或按照制造厂商建议的条件；所使用的原料、试剂等，如无特殊说明，视为可以通过常规市场等商业途径得到的原料和试剂。
核磁共振氢谱和碳谱于Bruker AVIII-500波谱仪上测试；红外光谱于NicoletMAGNA-IR 760红外光谱仪上测试；高分辨质谱于Bruker SolariX XR 7.0T FT-ICR-MS上测试。
反应方程式如下：
其中：R为H、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3或CH2CH2OH；R1为H或CN，R2为CN。
氰基取代二苯并呫吨化合物的制备方法，包括如下步骤：称取8mmol的二水合氯化铜，溶于15-20mL反应溶剂，然后加入8mmol的乙醇胺，加热至45℃搅拌使其混合均匀生成铜胺络合物。若溶液浑浊，补加反应溶剂，直至溶液澄清。称取1mmol的原料(6-氰基-2-萘酚或2-萘酚和6-氰基-2-萘酚的混合物)加入铜胺络合物中，溶解完全后，将反应容器置于微波炉中，以功率600-800W进行反应，TLC跟踪原料至反应完全，减压旋转蒸发回收大部分反应溶剂，加入质量分数为5％的氨水，用乙酸乙酯萃取三次，水洗有机层至中性，用无水Na2SO4干燥有机相，减压旋转蒸发回收乙酸乙酯，残留物进行硅胶柱层析，洗脱剂为石油醚-乙酸乙酯，得到产物。
下述实施例中优选微波炉的功率为700W。反应溶剂为甲醇、乙醇、正丙醇、异丙醇、正丁醇、乙二醇或水。
实施例1
原料为6-氰基-2-萘酚，反应溶剂为甲醇，得到化合物1a。
1-氧代-5,11-二氰基-13c-甲氧基-1,13c-二氢-二苯并[a,kl]-呫吨(1a)
黄色固体,Yield,75％,m.p.340.1-341.6℃,1H-NMR(300MHz,DMSO-d6)δ:8.70(s,1H),8.31(d,J＝9.0Hz,1H),8.10(d,J＝9.0Hz,1H),7.99(s,1H),7.87(s,1H),7.80(dd,J＝9.0Hz 1.8Hz,1H),7.69(d,J＝9.0Hz,1H),7.55(d,J＝10.2Hz,1H),6.53(d,J＝9.9Hz,1H),3.39(s,3H).13C-NMR(75MHz,DMSO-d6)δ:196.2,152.8,151.0,138.3,134.5,134.3,133.1,131.7,129.9,128.6,128.5,127.3,126.8,120.7,120.0,119.0,118.8,117.3,114.1,107.4,107.1,74.4,51.8.IR(KBr,cm-1)ν:3488,3073,2229,1706,1572,1383,1238,1053,821.HRMS calcd for C23H13N2O3[M+H]+365.09262,found[M+H]+365.09193.
实施例2
原料为6-氰基-2-萘酚，反应溶剂为乙醇，得到化合物1b。
1-氧代-5,11-二氰基-13c-乙氧基-1,13c-二氢-二苯并[a,kl]-呫吨(1b)
黄色固体,Yield,85％,m.p.182.7-183.5℃,1H-NMR(300MHz,Acetone-d6)δ:8.47(s,1H),8.26-8.22(m,2H),7.73-7.66(m,3H),7.59(d,J＝9.0Hz,1H),7.51(d,J＝6.9Hz,1H),6.42(d,J＝10.2Hz,1H),2.03-2.83(m,2H),0.91(t,J＝7.2Hz,3H).13C-NMR(75MHz,Acetone-d6)δ:195.8,152.9,151.4,137.9,135.1,135.0,134.1,132.9,130.5,129.2,127.1,126.9,126.3,121.1,120.4,119.0,118.5,117.0,114.8,108.6,108.3,74.5,60.5,14.7.IR(KBr,cm-1)ν:3448,3075,2972,2227,1716,1626,1573,1382,1239,1053,816.HRMScalcd for C24H15N2O3[M+H]+379.10827,found[M+H]+379.10772.
实施例3
原料为6-氰基-2-萘酚，反应溶剂为正丙醇，得到化合物1c。
1-氧代-5,11-二氰基-13c-正丙氧基-1,13c-二氢-二苯并[a,kl]-呫吨(1c)
黄色固体,Yield,75％,m.p.189.5-191.5℃,1H-NMR(300MHz,Acetone-d6)δ:8.48(s,1H),8.24(d,J＝9.0Hz,2H),7.74-7.66(m,3H),7.60(d,J＝8.7Hz,1H),7.41(d,J＝10.2Hz,1H),6.43(d,J＝10.2Hz,1H),2.89-2.81(m,2H),1.36-1.29(m,2H),0.63(t,J＝7.2Hz,3H).13C-NMR(75MHz,Acetone-d6)δ:198.5,152.9,151.5,137.9,135.1,134.9,134.1,132.8,130.5,129.2,127.2,126.8,126.3,121.1,120.4,119.1,118.5,117.0,114.8,108.6,108.3,74.4,66.7,22.6,10.0.IR(KBr,cm-1)ν:3448,3073,2961,2230,1703,1627,1572,1385,1237,1053,1005,810.HRMS calcd for C25H17N2O3[M+H]+393.12392,found[M+H]+393.12335.
实施例4
原料为6-氰基-2-萘酚，反应溶剂为异丙醇，得到化合物1d。
1-氧代-5,11-二氰基-13c-异丙氧基-1,13c-二氢-二苯并[a,kl]-呫吨(1d)
黄色固体,Yield,75％,m.p.222.5-224.2℃,1H-NMR(300MHz,Acetone-d6)δ:8.23(s,1H),8.09(d,J＝9.0Hz,1H),7.97(d,J＝9.0Hz,1H),7.56(s,1H),7.46-7.39(m,3H),7.21(d,J＝10.2Hz,1H),6.23(d,J＝10.2Hz,1H),2.84-2.46(m,1H),0.59(d,J＝6.3Hz,3H),0.42(d,J＝6.3Hz,3H).13C-NMR(75MHz,Acetone-d6)δ:195.0,152.5,151.3,136.9,135.5,135.1,133.8,132.5,130.5,130.0,127.5,126.3,125.8,121.5,120.4,118.7,118.3,116.8,115.0,109.8,108.7,74.2,68.6,22.9,22.9.IR(KBr,cm-1)ν:3422,3073,2974,2229,1709,1627,1572,1384,1237,1004,822.HRMS calcd for C25H17N2O3[M+H]+393.12392,found[M+H]+393.12342.
实施例5
原料为6-氰基-2-萘酚，反应溶剂为正丁醇，得到化合物1e。
1-氧代-5,11-二氰基-13c-正丁氧基-1,13c-二氢-二苯并[a,kl]-呫吨(1e)
黄色固体,Yield,75％,m.p.244.7-245.8℃,1H-NMR(300MHz,DMSO-d6)δ:8.60(s,1H),8.25-8.21(m,1H),8.05(t,J＝9.0Hz,1H),7.92(dd,J＝5.4Hz 1.8Hz,1H),7.80(s,1H),7.76-7.73(m,1H),7.64-7.59(m,1H),7.50(dd,J＝9.9Hz 1.8Hz,1H),6.44(dd,J＝10.5Hz 3.3Hz,1H),2.79-2.68(m,2H),1.21-1.15(m,2H),1.04-0.97(m,2H),0.51(t,J＝7.2Hz,3H).13C-NMR(75MHz,DMSO-d6)δ:196.2,152.4,151.0,138.3,134.5,134.3,133.1,132.9,129.9,128.5,127.3,126.9,126.5,120.7.119.0,118.8,117.3,114.1,114.0,107.8,107.4,73.9,63.9,30.8,18.4,13.1.IR(KBr,cm-1)ν:3422,3072,2958,2229,1706,1572,1380,1238,1053,822.HRMS calcd for C26H19N2O3[M+H]+407.13957,found[M+H]+407.13917.
实施例6
原料为6-氰基-2-萘酚，反应溶剂为乙二醇，得到化合物1f。
1-氧代-5,11-二氰基-13c-羟乙氧基-1,13c-二氢-二苯并[a,kl]-呫吨(1f)
黄色固体,Yield,48.1％,m.p.232.1-234.4℃,1H-NMR(500MHz,CDCl3)δ:8.23(d,J＝2Hz,1H),8.17(d,J＝9Hz,1H),8.00(d,J＝8.5Hz,1H),7.59(dd,J＝9Hz 2Hz,1H),7.48(dd,J＝5.5Hz1.5Hz,2H),7.39(d,J＝1.5Hz,1H),7.25(d,J＝10Hz,1H),6.41(d,J＝10Hz,1H),3.77-3.49(m,2H),3.06-2.98(m,1H),2.97-2.94(m,1H).13C-NMR(125MHz,CDCl3)δ:195.2,152.8,151.5,137.5,134.7,134.2,132.9,130.4,128.5,127.7,127.0,126.5,120.6,120.5,119.1,116.9,115.3,108.9,107.9,74.6,66.4,61.3,60.4.IR(KBr,cm-1)ν:3448,2923,2228,1708,1626,1573,1383,1239,1053,823.HRMS calcd for C24H15N2O4[M+H]+395.10318,found[M+H]+395.10353.
实施例7
原料为6-氰基-2-萘酚，反应溶剂为水，得到化合物1g。
1-氧代-5,11-二氰基-13c-羟基-1,13c-二氢-二苯并[a,kl]-呫吨(1g)
黄色固体,Yield,38.9％,m.p.175.3-177.2℃,1H-NMR(500MHz,DMSO-d6)δ:8.55(d,J＝1Hz,1H),8.14(d,J＝9Hz,1H),8.07(d,J＝9Hz,1H),7.84(d,J＝1Hz,1H),7.74(d,J＝1Hz,1H),7.69(d,J＝3Hz,1H),7.68(d,J＝1.5Hz,1H),7.55(d,J＝9Hz,1H),7.43(d,J＝10.5Hz,1H),6.41(d,J＝10Hz,1H).13C-NMR(125MHz,DMSO-d6)δ:198.8,150.9,149.4,138.4,135.1,135.0,134.8,132.5,130.4,130.1,127.4,126.3,125.4,121.2,119.6,119.5,118.0,113.7,112.8,107.4,68.3.IR(KBr,cm-1)ν:3387,3078,2227,1712,1571,1376,1242,1053,993,800.HRMS calcd for C22H11N2O3[M+H]+351.07697,found[M+H]+351.07642.
实施例8
原料为2-萘酚和6-氰基-2-萘酚，2-萘酚和6-氰基-2-萘酚的摩尔比为1.1:1，反应溶剂为甲醇，得到化合物2a。
1-氧代-11-氰基-13c-甲氧基-1,13c-二氢-二苯并[a,kl]-呫吨(2a)
黄色固体,Yield,89％,m.p.260.3-261.5℃,1H-NMR(300MHz,DMSO-d6)δ:8.59(s,1H),8.21(d,J＝9.0Hz,1H),8.07(d,J＝9.0Hz,1H),7.73(dd,J＝9.0Hz 1.8Hz,1H),7.62(d,J＝9.0Hz,1H),7.56(t,J＝7.5Hz,1H),7.46(d,J＝10.2Hz,1H),7.35-7.27(m,2H),6.33(d,J＝9.9Hz,1H),3.34(s,3H).13C-NMR(75MHz,DMSO-d6)δ:197.4,153.1,151.3,139.9,134.6,134.4,132.9,132.6,131.9,129.7,128.6,126.3,125.6,125.2,119.2,118.9,116.5,114.8,107.6,107.0,74.8,51.3.IR(KBr,cm-1)ν:3433,2932,2819,2226,1701,1628,1573,1454,1395,1251,1054,811.HRMS calcd for C22H14NO3[M+H]+340.09737,found[M+H]+340.09669.
实施例9
原料为2-萘酚和6-氰基-2-萘酚，2-萘酚和6-氰基-2-萘酚的摩尔比为1.1:1，反应溶剂为乙醇，得到化合物2b。
1-氧代-11-氰基-13c-乙氧基-1,13c-二氢-二苯并[a,kl]-呫吨(2b)
黄色固体,Yield,85％,m.p.280.3-282.4℃,1H-NMR(300MHz,Acetone-d6)δ:8.44(s,1H),8.28(d,J＝9.0Hz,1H),8.18(d,J＝9.0Hz,1H),7.65(dd,J＝9.0Hz 1.8Hz,1H),7.57-7.51(m,2H),7.41(d,J＝9.9Hz,1H),7.30(d,J＝9.0Hz,1H),7.21(dd,J＝8.4Hz1.2Hz,1H),6.27(d,J＝9.9Hz,1H),2.99-2.82(m,2H),0.89(t,J＝6.9Hz,3H).13C-NMR(75MHz,Acetone-d6)δ:197.9,154.1,152.6,140.3,136.2,134.9,134.5,133.2,132.4,131.1,130.2,126.8,126.7,125.7,120.1,119.6,117.3,117.1,110.1,108.8,68.1,60.9,15.7.IR(KBr,cm-1)ν:3435,2975,2871,2226,1704,1627,1572,1455,1394,1267,1054,811.HRMS calcd for C23H16NO3[M+H]+354.11302,found[M+H]+354.11229.
实施例10
原料为2-萘酚和6-氰基-2-萘酚，2-萘酚和6-氰基-2-萘酚的摩尔比为1.1:1，反应溶剂为正丙醇，得到化合物2c。
1-氧代-11-氰基-13c-正丙氧基-1,13c-二氢-二苯并[a,kl]-呫吨(2c)
黄色固体,Yield,82％,m.p.200.7-202.5℃,1H-NMR(300MHz,Acetone-d6)δ:8.44(s,1H),8.28(d,J＝9.0Hz,1H),8.18(d,J＝9.0Hz,1H),7.65(dd,J＝9.0Hz 2.1Hz,1H),7.57-7.51(m,2H),7.42(d,J＝9.9Hz,1H),7.41(d,J＝9.9Hz,1H),7.30(d,J＝6.9Hz,1H),7.23(dd,J＝8.4Hz 0.9Hz,1H),6.28(d,J＝9.9Hz,1H),2.85-2.75(m,2H),1.34-1.27(m,2H),0.62(t,J＝7.5Hz,3H).13C-NMR(75MHz,Acetone-d6)δ:197.9,154.1,152.6,140.3,136.2,134.9,134.5,133.2,132.4,131.1,130.3,126.8,126.8,125.7,120.1,119.6,117.3,117.1,110.0,108.8,75.7,66.9,23.6,11.0.IR(KBr,cm-1)ν:3448,2971,2926,2859,2224,1705,1627,1572,1455,1394,1266,1250,1006,811.HRMS calcd for C24H18NO3[M+H]+368.12867,found[M+H]+368.12790.
实施例11
原料为2-萘酚和6-氰基-2-萘酚，2-萘酚和6-氰基-2-萘酚的摩尔比为1.1:1，反应溶剂为异丙醇，得到化合物2d。
1-氧代-11-氰基-13c-异丙氧基-1,13c-二氢-二苯并[a,kl]-呫吨(2d)
黄色固体,Yield,85％,m.p.280.6-281.9℃,1H-NMR(300MHz,Acetone-d6)δ:8.44(s,1H),8.25(d,J＝9.0Hz,1H),8.19(d,J＝9.0Hz,1H),7.65(dd,J＝9.0Hz 1.8Hz,1H),7.56(t,J＝8.1Hz,2H),7.39(d,J＝9.9Hz,1H),7.30(dd,J＝10.2Hz 0.9Hz,1H),7.27-7.24(m,2H),6.27(d,J＝10.2Hz,1H),3.49-3.41(m,1H),0.70(t,J＝6.0Hz,3H),0.52(t,J＝6.0Hz,3H).13C-NMR(75MHz,Acetone-d6)δ:197.9,153.8,152.4,151.3,139.8,136.3,135.0,134.9,133.2,132.4,131.1,127.0,126.5,125.5,120.2,119.6,117.6,117.5,111.2,108.8,75.6,68.8,23.9,23.8.IR(KBr,cm-1)ν:3407,2977,2926,2227,1714,1626,1573,1454,1381,1351,1267,1249,999,812.HRMS calcd for C24H18NO3[M+H]+368.12867,found[M+H]+368.12789.
实施例12
原料为2-萘酚和6-氰基-2-萘酚，2-萘酚和6-氰基-2-萘酚的摩尔比为1.1:1，反应溶剂为正丁醇，得到化合物2e。
1-氧代-11-氰基-13c-正丁氧基-1,13c-二氢-二苯并[a,kl]-呫吨(2e)
黄色固体,Yield,82％,m.p.190.5-192.3℃,1H-NMR(300MHz,Acetone-d6)δ:8.44(s,1H),8.28(d,J＝9.0Hz,1H),8.18(d,J＝9.0Hz,1H),7.65(dd,J＝9.0Hz 2.1Hz,1H),7.53(dd,J＝9.0Hz1.8Hz,1H),7.42(d,J＝9.9Hz,1H),7.41(d,J＝9.9Hz,1H),7.30(d,J＝6.9Hz,1H),7.23(dd,J＝8.4Hz 0.9Hz,1H),6.28(d,J＝9.9Hz,1H),2.85-2.75(m,2H),1.34-1.27(m,2H),0.62(t,J＝7.5Hz,3H).13C-NMR(75MHz,Acetone-d6)δ:197.9,154.1,152.6,140.3,136.2,134.9,134.5,133.2,132.4,131.1,130.3,126.8,126.8,125.7,120.1,119.6,117.3,117.1,110.0,108.8,75.7,66.9,23.6,11.0.IR(KBr,cm-1)ν:3448,2958,2866,2224,1704,1627,1572,1455,1393,1352,1267,1250,1033,814.HRMS calcdfor C25H20NO3[M+H]+382.14432,found[M+H]+382.14350.
实施例13
原料为2-萘酚和6-氰基-2-萘酚，2-萘酚和6-氰基-2-萘酚的摩尔比为1.1:1，反应溶剂为乙二醇，得到化合物2f。
1-氧代-11-氰基-13c-羟乙氧基-1,13c-二氢-二苯并[a,kl]-呫吨(2f)
黄色固体,Yield,39.7％,m.p.178.9-181.1℃,1H-NMR(500MHz,Acetone-d6)δ:8.43(d,J＝2Hz,1H),8.31(d,J＝8.5Hz,1H),8.19(d,J＝9Hz,1H),7.61(dd,J＝9Hz 2Hz,1H),7.56(d,J＝6Hz,1H),7.59-7.53(m,1H),7.40(d,J＝10Hz,1H),7.24(dd,J＝8.5Hz1Hz,1H),7.23(d,J＝0.5Hz,1H),6.25(d,J＝10Hz,1H),3.39-3.37(m,2H),3.01-2.97(m,1H),2.90-2.86(m,1H).13C-NMR(125MHz,Acetone-d6)δ:196.7,153.3,151.7,139.4,135.3,133.9,133.6,132.4,131.6,130.3,129.6,125.9,125.8,124.9,119.2,118.7,116.5,116.0,108.9,108.0,74.9,66.2,60.5.IR(KBr,cm-1)ν:3510,2923,2851,2223,1698,1626,1570,1455,1395,1268,1081,1064,813.HRMS calcd for C23H16NO4[M+H]+370.10793,found[M+H]+370.10738.
实施例14
原料为2-萘酚和6-氰基-2-萘酚，2-萘酚和6-氰基-2-萘酚的摩尔比为1.1:1，反应溶剂为水，得到化合物2g。
1-氧代-11-氰基-13c-羟基-1,13c-二氢-二苯并[a,kl]-呫吨(2g)
砖红色固体,Yield,61.3％,m.p.199.6-202.1℃,1H-NMR(500MHz,DMSO-d6)δ:8.55(d,J＝1.5Hz,1H),8.14(d,J＝1.5Hz,1H),8.12(d,J＝1Hz,1H),7.68(dd,J＝9Hz 2Hz,1H),7.56(d,J＝9Hz,1H),7.47(t,J＝7.5Hz,1H),7.41(t,J＝10Hz,1H),7.28(d,J＝7Hz,1H),7.24(d,J＝1Hz,1H),7.22(d,J＝0.5Hz,1H),6.29(d,J＝10Hz,1H).13C-NMR(125MHz,DMSO-d6)δ:199.9,151.2,149.6,140.0,135.4,134.7,133.6,132.0,126.1,126.0,125.2,120.5,119.8,119.6,117.1,113.3,107.0,68.5.IR(KBr,cm-1)ν:3559,2923,2852,2224,1701,1629,1569,1456,1397,1269,1166,1032,813.HRMS calcd for C21H12NO3[M+H]+326.08172,found[M+H]+326.08117.
实验例1
氰基取代二苯并呫吨化合物抗肿瘤活性试验
采用MTT实验对实施例1-14得到的部分氰基取代二苯并呫吨化合物体外抑制肿瘤细胞生长进行检测。
分别选取HeLa(人宫颈癌细胞株)、HepG2(人肝癌细胞株)、A549(人肺癌细胞株)、SGC-7901(人胃癌细胞株)及LO2(人正常肝细胞株)进行了筛选。具体方法为：将处于对数生长期的各肿瘤细胞株按8×104个/孔的细胞量接种至96孔板中，放置于培养箱中孵育24h，更换培养液后加入浓度梯度的各药物，使药物终浓度为10-6-10-4mol/L，每组设置3个平行复孔，且设置培养液空白对照孔。然后在培养箱中孵育48h，各孔都加入不含血清的培养基90μL和浓度为5mg/mL的MTT溶液10μL，然后在培养箱中培养4h，加入100μL DMSO微量振荡器中震荡15min后，采用酶标仪490nm处测定吸光度值。按下式计算细胞成活率：细胞成活率(％)＝(实验组)/空白组)×100％。将各组药物的浓度与所对应的细胞成活率绘制出细胞生长曲线，从中读出当细胞成活率为50％时所对应的化合物浓度，该浓度即为IC50值。结果参见表2。
表2氰基取代二苯并呫吨化合物对肿瘤细胞的IC50值(μmol/L)
由表2得出，化合物1a～1e、2a～2c和2e对四种肿瘤细胞均显示较高的抑制活性，化合物2d对HeLa、HepG2、A549及LO2的IC50值(Dark)均>100μmol/L，而对SGC-7901则有较强的抑制活性，显示出良好的选择性。
以上实施例的说明只是用于帮助理解本发明的技术方案及其核心思想，应当指出，对于本技术领域的技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (10)
1.式(Ⅰ)所示的氰基取代二苯并呫吨化合物：
其中：R为H、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3或CH2CH2OH；R1为H或CN，R2为CN。
2.根据权利要求1所述的氰基取代二苯并呫吨化合物，其特征在于，式(Ⅰ)所示的氰基取代二苯并呫吨化合物如下表所示：
3.权利要求1或2所述的氰基取代二苯并呫吨化合物的制备方法，其特征在于，包括如下步骤：称取二水合氯化铜，溶于反应溶剂，然后加入乙醇胺，加热搅拌使其混合均匀生成铜胺络合物溶液，二水合氯化铜与乙醇胺的摩尔比为1:1，若溶液浑浊，补加反应溶剂，直至溶液澄清，称取原料加入铜胺络合物中，所述的原料为6-氰基-2-萘酚或2-萘酚和6-氰基-2-萘酚的混合物，溶解完全后，将反应容器置于微波反应容器中，TLC跟踪原料至反应完全，减压蒸馏，乙酸乙酯萃取，有机相用无水硫酸钠干燥，旋干，所得粗产品进行硅胶柱层析分离和洗脱，得到产物；
上述反应所涉及的反应方程式如下：
其中：R为H、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3或CH2CH2OH；R1为H或CN，R2为CN。
4.根据权利要求3所述的方法，其特征在于，所述的2-萘酚与6-氰基-2-萘酚的摩尔比为1.1:1。
5.根据权利要求3或4所述的方法，其特征在于，所述的二水合氯化铜或乙醇胺与原料的摩尔比为1:1。
6.根据权利要求3或4所述的方法，其特征在于，所述的反应溶剂为水或ROH，R为CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3或CH2CH2OH。
7.根据权利要求3或4所述的方法，其特征在于，所述的洗脱剂为石油醚-乙酸乙酯。
8.权利要求1或2所述的氰基取代二苯并呫吨化合物在制备抗肿瘤药物中的应用。
9.根据权利要求8所述的应用，其特征在于，所述的应用具体为氰基取代二苯并呫吨化合物在制备抗宫颈癌药物、抗肝癌药物、抗胃癌药物或抗肺癌药物中的应用。
10.含有权利要求1或2所述的氰基取代二苯并呫吨化合物及其药学上可接受的盐组合成的药学上可接受的药物组合物或制剂在制备抗肿瘤药物的应用。
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